Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration

ABSTRACT

The present invention provides a pharmaceutical composition for nasal administration comprising mometasone furoate and azelastine hydrochloride, wherein the pharmaceutical composition comprises thaumatin as an agent for reducing bitterness and irritation.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition for nasaladministration comprising mometasone furoate and azelastinehydrochloride. More specifically, the present invention relates to apharmaceutical composition whose nasal sensation is improved by reducingbitterness and irritation of azelastine hydrochloride through the use ofthaumatin.

BACKGROUND ART

Mometasone furoate, one of the steroids used for treating allergicrhinitis, is known to be highly effective in prolonged symptom-relief.Azelastine hydrochloride, one of the short-acting antihistamines, isknown to be highly effective in immediate symptom-improvement.Therefore, co-administration of these two drugs in a combinationformulation is expected to exhibit an excellent effect in the long-termtreatment of allergic rhinitis, along with immediate symptomaticimprovement. International Publication WO97/01337 has disclosed a nasalspray or nasal drop formulation comprising azelastine or its salt; andbeclomethasone, flunisolide, triamcinolone, dexamethasone or budesonide.And also, International Publication WO2003/105856 has disclosed apharmaceutical formulation suitable for nasal or ocular administration(e.g., a nasal spray), which comprises azelastine or its salt; and asteroid such as mometasone furoate.

Meanwhile, azelastine hydrochloride has strong bitter taste. The degreeof the bitter taste is so intense that it is even found to be unpleasantin a dilution of 1×10⁶ time (U.S. Pat. No. 5,164,194). After azelastinehydrochloride is intranasally applied, such a bitterness of azelastinehydrochloride is delivered to the pharynx, thereby causing unpleasanttaste and irritation. U.S. Pat. No. 6,576,677 has disclosed a use ofpolyvinylpyrrolidone and/or copolyvidone for alleviating the unpleasanttaste of azelastine hydrochloride. And also, International PublicationWO2006/058022 has disclosed a pharmaceutical composition comprisingazelastine hydrochloride and mometasone furoate, wherein sucralose isused as an agent for masking bitterness.

DISCLOSURE Technical Problem

The present invention provides a pharmaceutical composition for nasaladministration comprising mometasone furoate and azelastinehydrochloride, the nasal sensation of which is improved by reducingbitterness and irritation of azelastine hydrochloride through the use ofthaumatin extracted from a natural source, i.e., Thaumatococcusdaniellii Benth.

That is, it is an object of the present invention to provide apharmaceutical composition for nasal administration comprisingmometasone furoate and azelastine hydrochloride, in which thaumatin isused as an agent for reducing bitterness and irritation.

Technical Solution

In accordance with an aspect of the present invention, there is provideda pharmaceutical composition for nasal administration comprisingmometasone furoate and azelastine hydrochloride, wherein thepharmaceutical composition comprises thaumatin as an agent for reducingbitterness and irritation. In the pharmaceutical composition for nasaladministration according to the present invention, the thaumatin may bepresent in an amount ranging from 0.1 to 0.5 w/v %.

In an embodiment of the present invention, there is provided apharmaceutical composition comprising 0.01 to 1.0 w/v % of mometasonefuroate; 0.05 to 1.0 w/v % of azelastine hydrochloride; 0.1 to 0.5 w/v %of thaumatin; 1.0 to 5.0 w/v % of a thickening agent; 0.2 to 0.6 w/v %of a buffering agent; 0.001 to 0.1 w/v % of a surfactant; 5.0 to 10.0w/v % of an isotonic agent; 0.01 to 1.0 w/v % of a stabilizer; and 0.002to 0.05 w/v % of a preservative, in an aqueous medium. In a preferableembodiment, there is provided a pharmaceutical composition consisting of0.05 w/v % of mometasone furoate; 0.14 w/v % of azelastinehydrochloride; 0.25 w/v % of thaumatin; 2.0 w/v % of a mixture ofmicrocrystalline cellulose and sodium carboxymethyl cellulose; 0.2 w/v %of citric acid;

0.28 w/v % of sodium citrate; 0.01 w/v % of polyoxyethylene sorbitanmonooleate; 2.1 w/v % of glycerin; 6.6 w/v % of sorbitol; 0.1 w/v % ofsodium edetate; 0.02 w/v % of benzalkonium chloride; and the remainingamount of water.

The pharmaceutical composition may be administered preferably in a nasalspray form.

Advantageous Effects

It has been found by the present invention that thaumatin effectivelyreduces the bitterness and irritation of azelastine hydrochloride,thereby providing excellent nasal sensation when intranasallyadministered. Therefore, patients' drug compliance can be increased byformulating mometasone furoate and azelastine hydrochloride through theuse of thaumatin as an agent for reducing bitterness and irritation; andthen administering the resulting formulation intranasally. In addition,the pharmaceutical composition for nasal administration comprisingmometasone furoate and azelastine hydrochloride, which is formulatedwith thaumatin according to the present invention, has excellentstability.

BEST MODE

The present invention provides a pharmaceutical composition for nasaladministration comprising mometasone furoate and azelastinehydrochloride, wherein the pharmaceutical composition comprisesthaumatin as an agent for reducing bitterness and irritation.

Said “thaumatin” is a protein mixture obtained by extracting the seed ofThaumatococcus daniellii Benth (plant of West Africa) with water andthen purifying the extract. The protein mixture comprises 5 proteins,i.e., thaumatin I, II, III, a, and b, mainly thaumatin I and II.Thaumatin I and II have the almost same amino acid sequences. Thaumatinis listed in the Korea Food Additives Code; and being used in ices,refreshing beverages, etc., as a sweetening or flavor agent. It is knownthat thaumatin is a protein produced against the attack of viroidpathogens. Thaumatins exhibit an inhibitory activity against the hyphagrowh and sporulation of fungi.

It has been found by the present invention that thaumatin effectivelyreduces the bitterness and irritation of azelastine hydrochloride,thereby providing excellent nasal sensation when intranasallyadministered. In the pharmaceutical composition according to the presentinvention, the thaumatin may be present in an amount ranging from 0.1 to0.5 w/v %, preferably from 0.2 to 0.4 w/v %, more preferably about 0.25w/v %, based on total volume of the composition.

In the pharmaceutical composition for nasal administration according tothe present invention, mometasone furoate, one of the activeingredients, may be present in an amount ranging from 0.01 to 1.0 w/v %,preferably in an amount ranging from 0.05 to 0.5 w/v %, more preferablyin an amount of about 0.05 w/v %, based on total volume of thecomposition. And also, azelastine hydrochlorid, another activeingredient, may be present in an amount ranging from 0.05 to 1.0 w/v %,preferably in an amount ranging from 0.1 to 0.5 w/v %, more preferablyin an amount of about 0.14 w/v %, based on total volume of thecomposition.

The pharmaceutical composition for nasal administration according to thepresent invention may include excipients conventionally used informulations for nasal administration, such as thickening agents,buffering agents, surfactants, isotonic agents, stabilizers,preservatives, etc.

As a thickening agent, a mixture of microcrystalline cellulose andsodium carboxymethyl cellulose (for example, Avicel RC 591, Avicel RC581, Avicel CL 611, etc.) may be used. The thickening agent may be usedin an amount ranging from 1.0 to 5.0 w/v %, preferably in an amountranging from 1.0 to 4.0 w/v %, more preferably in an amount of about 2.0w/v %, based on total volume of the composition, although the amountthereof varies according the thickening agent used.

As a buffering agent, a combination of acid and its salt (for example, acombination of citric acid and sodium citrate) may be used. Thebuffering agent may be used in an amount ranging from 0.2 to 0.6 w/v %,preferably in an amount ranging from 0.3 to 0.5 w/v %, based on totalvolume of the composition, although the amount thereof varies accordingthe buffering agent used, buffer strength, etc. In an embodiment, acombination of about 0.2 w/v % of citric acid (or its hydrate) and 0.28w/v % of sodium citrate (or its hydrate), based on total volume of thecomposition, may be used.

A surfactant facilitates the suspension of mometasone furoate, one ofthe sparingly water-soluble drugs. As a surfactant, polyoxyethylenesorbitan monooleate (for example, Polysorbate 40, Polysorbate 60,Polysorbate 80, etc.) may be used. The surfactant may be used in anamount ranging from 0.001 to 0.1 w/v %, preferably in an amount rangingfrom 0.005 to 0.05 w/v %, more preferably in an amount of about 0.01 w/v%, based on total volume of the composition, although the amount thereofvaries according the buffering agent used.

As an isotonic agent, glycerin, sorbitol, or a combination of glycerinand sorbitol may be used. Since the use of saccharides can additionallyprovide sweet taste, saccharides (such as sorbitol) may be preferablyused. The isotonic agent may be used in an amount ranging from 5.0 to10.0 w/v %, preferably in an amount ranging from 6.0 to 9.0 w/v %, basedon total volume of the composition, although the amount thereof variesaccording the isotonic agent used. In an embodiment, a combination ofabout 2.1 w/v % of glycerin and 6.6 w/v % of sorbitol (e.g.,D-sorbitol), based on total volume of the composition, may be used.

As a stabilizer, sodium edetate or its hydrate may be used. Thestabilizer may be used in an amount ranging from 0.01 to 1.0 w/v %,preferably in an amount of about 0.1 w/v %, based on total volume of thecomposition. In addition, as a preservative, conventional preservativessuch as benzalkonium chloride may be used in an amount ranging from0.002 to 0.05 w/v %, preferably in an amount of about 0.02 w/v, based ontotal volume of the composition.

In an embodiment of the present invention, there is provided apharmaceutical composition for nasal administration comprising 0.01 to1.0 w/v % of mometasone furoate; 0.05 to 1.0 w/v % of azelastinehydrochloride; 0.1 to 0.5 w/v % of thaumatin; 1.0 to 5.0 w/v % of athickening agent; 0.2 to 0.6 w/v % of a buffering agent; 0.001 to 0.1w/v % of a surfactant; 5.0 to 10.0 w/v % of an isotonic agent; 0.01 to1.0 w/v % of a stabilizer; and 0.002 to 0.05 w/v % of a preservative, inan aqueous medium (for example, purified water etc.).

In another embodiment of the present invention, there is provided apharmaceutical composition for nasal administration comprising 0.01 to1.0 w/v % of mometasone furoate; 0.05 to 1.0 w/v % of azelastinehydrochloride; 0.1 to 0.5 w/v % of thaumatin; 1.0 to 5.0 w/v % of amixture of microcrystalline cellulose and sodium carboxymethylcellulose; 0.2 to 0.6 w/v % of a mixture of citric acid and sodiumcitrate; 0.001 to 0.1 w/v % of polyoxyethylene sorbitan monooleate; 5.0to 10.0 w/v % of a mixture of glycerin and sorbitol; 0.01 to 1.0 w/v %of sodium edetate; and 0.002 to 0.05 w/v % of benzalkonium chloride, inan aqueous medium (for example, purified water etc.).

In preferable embodiment of the present invention, there is provided apharmaceutical composition for nasal administration consisting of 0.05w/v % of mometasone furoate; 0.14 w/v % of azelastine hydrochloride;0.25 w/v % of thaumatin;

2.0 w/v % of a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose; 0.2 w/v % of citric acid; 0.28 w/v % of sodiumcitrate; 0.01 w/v % of polyoxyethylene sorbitan monooleate; 2.1 w/v % ofglycerin; 6.6 w/v % of sorbitol; 0.1 w/v % of sodium edetate; 0.02 w/v %of benzalkonium chloride; and the remaining amount of water.

The pharmaceutical composition for nasal administration according to thepresent invention may be administered preferably in a nasal spray form.Therefore, the pharmaceutical composition of the present invention maybe formulated preferably into a nasal spray form.

The present invention will be described in further detail with referenceto the following examples. These examples are for illustrative purposesonly and are not intended to limit the scope of the present invention.

EXAMPLES 1 AND 2 Suspensions for Nasal Spray

Suspensions for nasal spray were prepared according to the componentsand amounts shown in Table 1 below. Each amount of Table 1 refers to anamount in w/v %.

Avicel RC 591 and glycerin were dispersed in sterile purified water witha Homo Mixer (Mixture I). In a separate vessel, azelastinehydrochloride, benzalkonium chloride, citric acid hydrate, sodiumcitrate hydrate, sodium edetate hydrate, D-sorbitol and thaumatin weredissolved in sterile purified water under stirring the mixture (MixtureII). In a separate vessel, mometasone furoate and Polysorbate 80 weredispersed in sterile purified water (Mixture III). The mixture I wasmixed with the mixture II under stirring; and the resulting mixture wasthen mixed with the mixture III under stirring. Sterile purified waterwas added to the resulting mixture, to adjust the final volume.

TABLE 1 Component Example 1 Example 2 Mometasone furoate EP 0.05 0.05Azelastine hydrochloride EP 0.14 0.14 Avicel RC 591 NF 2.0 2.0 GlycerinUSP 2.1 2.1 Sodium edetate hydrate KP 0.1 0.1 Citric acid hydrate KP 0.20.2 Sodium citrate hydrate KP 0.28 0.28 Polysorbate 80 KP 0.01 0.01Benzalkonium chloride KP 0.02 0.02 D-sorbitol USP 6.6 6.6 Thaumatin KPC0.25 0.125 Sterile purified water KP Remaining amount Remaining amount(adjusted to 100%) (adjusted to 100%)

COMPARATIVE EXAMPLES 1 TO 3

Suspensions for nasal spray were prepared according to the componentsand amounts shown in Table 2 below, using various artificial sweeteningagents instead of thaumatin, in the same manner as in Example 1. Eachamount of Table 2 refers to an amount in w/v %.

TABLE 2 Comparative Comparative Comparative Component Example 1 Example2 Example 3 Mometasone furoate EP 0.05 0.05 0.05 Aazelastinehydrochloride EP 0.14 0.14 0.14 Avicel RC 591 NF 2.0 2.0 2.0 GlycerinUSP 2.1 2.1 2.1 Sodium edetate hydrate KP 0.1 0.1 0.1 Citric acidhydrate KP 0.2 0.2 0.2 Sodium citrate hydrate KP 0.28 0.28 0.28Polysorbate 80 KP 0.01 0.01 0.01 Bbenzalkonium chloride KP 0.02 0.020.02 D-sorbitol USP 6.6 6.6 6.6 Neohesperidin 0.25 — — Sucralose NF —0.25 — Acesulfame potassium — — 0.25 Sterile purified water KP RemainingRemaining Remaining amount amount amount (adjusted to (adjusted to(adjusted to 100%) 100%) 100%)

EXPERIMENTAL EXAMPLE 1 Evaluation of Nasal Sensation

Nasal sensation was evaluated based on the 4 items, i.e., “bitternessfelt”, “sweetness felted”, “irritation”, and “persistence ofirritation”. The evaluation grades of each item were assigned 1 to 5from ‘weak’ to ‘strong’. That is, in the items of “bitterness felt”,“sweetness felted”, or “irritation”, the evaluation grade ‘1’ means“weak bitterness was felt”, “weak sweetness was felted”, or “there wasweak irritation”, while the evaluation grade ‘5’ means “strongbitterness was felt”, “strong sweetness was felted”, or “there wasstrong irritation”. And also, in the item of “persistence ofirritation”, the evaluation grade ‘1’ means “irritation was persistedshortly”, while the evaluation grade ‘5’ means “irritation was persistedfor long duration”.

Each suspension prepared in Example 1 and Comparative Examples 1 to 3was filled into a vessel for nasal spray; and then intranasally sprayedto 30 volunteers for 10 seconds. The evaluation of nasal sensationregarding the above items was performed; and the results thereof areshown in Table 3 below. The results of Table 3 refer to a mean value ofthe evaluation grades in each item.

TABLE 3 Bitterness Sweetness Persistence of felt felt Irritationirritation Example 1 2.1 3.9 1.8 1.9 Comparative 4.2 2.2 3.2 1.8 Example1 Comparative 2.4 4.5 3.2 3.1 Example 2 Comparative 2.9 4.2 3.4 3.6Example 3

As seen from the results of Table 3, the composition containingthaumatin according to the present invention showed almost no bitternessand relatively strong sweetness; and also showed excellent propertiesespecially in the irritation item and the persistence-of-irritationitem. The composition containing neohesperidin, which is one of theartificial sweetening agents, (i.e., Comparative Example 1) showed verypoor masking effects against the bitter taste and irritation derivedfrom azelastine hydrochloride. And also, the composition containingsucralose (i.e., Comparative Example 2) showed relatively goodbitterness-masking effects, but very poor irritation-masking effects.The composition containing acesulfame potassium (i.e., ComparativeExample 3) showed not only very poor irritation-masking effects, butalso persisted-irritations for long duration. Therefore, it can be seenthat the composition containing thaumatin according to the presentinvention exhibits excellent nasal sensation, in comparison with thosecontaining other sweetening agents.

EXPERIMENTAL EXAMPLE 2 Mucosal Irritation Tests

Irritancy tests on the ocular mucosa were carried out as a mucosalirritation test, because the ocular mucosa is more sensitive toirritation than the nasal mucosa; and the well established-test methodthereof makes it easy to interpret the results. The tests were carriedout in accordance with the internal management protocol (10-BL-455protocol). The preparation of this protocol and the test-performing wereconducted in accordance with the Guideline on Toxicity Study of Drugs(No. 2009-116, KFDA, 4 Aug. 2009), the Good Laboratory Practice (No.2009-183, KFDA, 22 Dec. 2009), and the OECD Principles of GoodLaboratory Practice (1997). The suspension of Example 1 was administeredto the ocular mucosa of New Zealand White rabbits, in a dose of 0.1mL/head; and then the symptoms thereof were observed for 7 days.

The results were as follows: (1) any general symptom(s) and animal deathassociated with the application of the test material was not observedduring the test period; (2) any body weight change associated with theapplication of the test material was not observed during the testperiod; (3) any change was not observed in both the eye-washing groupand non-eye-washing group, as a result of the observation of ocularreaction after the application of the test material; (4) the Index ofAcute Ocular Irritation (I.A.O.I) was evaluated as zero (i.e.,non-irritant) during the test period, as a result of the observation ofocular reaction after the application of the test material.

Therefore, the pharmaceutical composition prepared according to thepresent invention was found to be non-irritant, when applied to theocular mucosa; and therefore it was also found that it would not causeany irritation, even when applied to the nasal cavity.

EXPERIMENTAL EXAMPLE 3 Physical and Chemical Stability Tests

(1) Long-Term Storage Test

Stability tests according to long-term storage were carried out, whilethe suspension prepared in Example 1 was maintained under the conditionsof 20±5° C. and 60% relative humidity for 24 months. Appearance wasobserved with the naked eyes; and the pH was measured with a pH meter.Both the quantitative analyses of azelastine hydrochloride and itsdegradation products and the quantitative analyses of mometasone furoateand its degradation products were carried out with a high-performanceliquid chromatography (HPLC), under the following HPLC conditions:

<HPLC Conditions for Quantitative Analyses of Azelastine Hydrochlorideand Its Degradation Products>

-   -   Column: Capcellpak C₁₈ Column (4.6×250 mm, 5 μm)    -   Column Temperature: 30° C.    -   Detector: UV spectrophotometer (wavelength: 212 nm)    -   Mobile phase: prepared by adding 941.1 mg of sodium        1-hexanesulfonate to 1 L of 40% acetonitrile solution.

<HPLC Conditions for Quantitative Analyses of Mometasone Furoate and ItsDegradation Products>

-   -   Column: Capcellpak C₁₈ Column(4.6×150 mm, 5 μm)    -   Column Temperature: 30° C.    -   Detector: UV spectrophotometer (wavelength: 254 nm)    -   Mobile phase: a mixed solvent of water and acetonitrile (50/50)

The results of stability tests according to long-term storage under theconditions of 20±5° C. and 60% relative humidity for 24 months are shownin Table 4 below.

TABLE 4 3 6 9 12 18 24 Criteria Initial months months months monthsmonths months Appearance White The same The same The same The same Thesame The same The same non-transparent as on as on as on as on as on ason as on suspension the left the left the left the left the left theleft the left pH 4.0-6.0 4.67 4.65 4.60 4.57 4.55 4.51 4.49 Azelastinehydrochloride Degradation Degradation Not Not Not Not Not Not Notproduct products A, B, C: detected detected detected detected detecteddetected detected not more than 0.2% Unknown maximum 0.01% 0.01% 0.01%0.01% 0.01% 0.02% 0.02% degradation product: not more than 0.2% Totaldegradation 0.01% 0.01% 0.01% 0.01% 0.01% 0.02% 0.02% products: not morethan 1.0% Contents 90.0-110.0% of 99.2% 100.3% 100.1% 100.0% 99.4% 99.6%100.0% the labeled amount Mometasone furcate Degradation Unknown maximum0.02% 0.02% 0.03% 0.03% 0.03% 0.05% 0.05% product degradation product:not more than 0.1% Total degradation 0.02% 0.02% 0.03% 0.03% 0.03% 0.05%0.05% products: not more than 0.6% Contents 90.0-110.0% of 99.7% 99.3%99.6% 99.7% 99.5% 99.4% 99.6% the labeled amount

From the results of Table 4, it can be seen that the composition of thepresent invention has excellent physical and chemical stabilities for 24months.

(2) Accelerated Tests

Accelerated tests were carried out, while the suspension prepared inExample 1 was maintained under the conditions of 40 ° C. and 75%relative humidity for 6 months. The observation of appearance, the pHmeasurement, the quantitative analyses of azelastine hydrochloride andits degradation products, and the quantitative analyses of mometasonefuroate and its degradation were performed in the same manners as in theabove (1). The results are shown in Table 5 below.

TABLE 5 Criteria Initial 1 month 3 months 6 months Appearance Whitenon-transparent The same The same The same The same suspension as on theas on the as on the as on the left left left left pH 4.0-6.0 4.67 4.624.53 4.48 Azelastine hydrochloride Degradation Degradation products A,B, C: Not Not Not Not product not more than 0.2% detected detecteddetected detected Unknown maximum degradation 0.01% 0.01% 0.02% 0.02%product: not more than 0.2% Total degradation products: 0.01% 0.01%0.02% 0.04% not more than 1.0% Contents 90.0-110.0% of the labeled 99.2%100.3%  99.7% 99.1% amount Mometasone furoate Degradation Unknownmaximum degradation 0.02% 0.03% 0.03% 0.05% product product: not morethan 0.1% Total degradation products: not 0.02% 0.04% 0.04% 0.06% morethan 0.6% Contents 90.0-110.0% of the labeled 99.7% 99.4% 99.2% 99.0%amount

From the results of Table 5, it can be seen that the composition of thepresent invention also has excellent physical and chemical stabilitiesin the accelerated test for 6 months.

1. A pharmaceutical composition for nasal administration comprisingmometasone furoate azelastine hydrochloride and thaumatin for reducingbitterness and irritation.
 2. The pharmaceutical composition for nasaladministration of claim 1, wherein the thaumatin is present in an amountfrom 0.1 to 0.5 w/v %.
 3. The pharmaceutical composition for nasaladministration of claim 1, wherein the pharmaceutical compositioncomprises 0.01 to 1.0 w/v % of mometasone furoate; 0.05 to 1.0 w/v % ofazelastine hydrochloride; 0.1 to 0.5 w/v % of thaumatin; 1.0 to 5.0 w/v% of a thickening agent; 0.2 to 0.6 w/v % of a buffering agent; 0.001 to0.1 w/v % of a surfactant; 5.0 to 10.0 w/v % of an isotonic agent; 0.01to 1.0 w/v % of a stabilizer; and 0.002 to 0.05 w/v % of a preservative,in an aqueous medium.
 4. The pharmaceutical composition for nasaladministration of claim 3, wherein the pharmaceutical compositioncomprises 0.01 to 1.0 w/v % of mometasone furoate; 0.05 to 1.0 w/v % ofazelastine hydrochloride; 0.1 to 0.5 w/v % of thaumatin; 1.0 to 5.0 w/v% of a mixture of microcrystalline cellulose and sodium carboxymethylcellulose; 0.2 to 0.6 w/v % of a mixture of citric acid and sodiumcitrate; 0.001 to 0.1 w/v % of polyoxyethylene sorbitan monooleate; 5.0to 10.0 w/v % of a mixture of glycerin and sorbitol; 0.01 to 1.0 w/v %of sodium edetate; and 0.002 to 0.05 w/v % of benzalkonium chloride, inan aqueous medium.
 5. The pharmaceutical composition for nasaladministration of claim 4, wherein the pharmaceutical compositionconsists of 0.05 w/v % of mometasone furoate;
 0. 14 w/v % of azelastinehydrochloride; 0.25 w/v % of thaumatin; 2.0 w/v % of a mixture ofmicrocrystalline cellulose and sodium carboxymethyl cellulose; 0.2 w/v %of citric acid; 0.28 w/v % of sodium citrate; 0.01 w/v % ofpolyoxyethylene sorbitan monooleate; 2.1 w/v % of glycerin; 6.6 w/v % ofsorbitol; 0.1 w/v % of sodium edetate; 0.02 w/v % of benzalkoniumchloride; and the remaining amount of water.
 6. The pharmaceuticalcomposition for nasal administration according to claim 1, wherein thepharmaceutical composition is formulated into a nasal spray form.
 7. Thepharmaceutical composition for nasal administration according to claim2, wherein the pharmaceutical composition is formulated into a nasalspray form.
 8. The pharmaceutical composition for nasal administrationaccording to claim 3, wherein the pharmaceutical composition isformulated into a nasal spray form.
 9. The pharmaceutical compositionfor nasal administration according claim 4, wherein the pharmaceuticalcomposition is formulated into a nasal spray form.
 10. Thepharmaceutical composition for nasal administration according claim 5,wherein the pharmaceutical composition is formulated into a nasal sprayform.